Hsp90 is a molecular chaperone with important roles in regulating transformation in biological systems. While its involvement in maintaining the malignant phenotype has been extensively studied, deciphering its role in other transformed systems has lagged behind. Recent evidence from the collaborative efforts of Chiosis and Greengard laboratories suggests a role for Hsp90 in maintaining the functional stability of neuronal proteins of aberrant capacity, whether mutated or over-activated, allowing and sustaining the accumulation of toxic aggregates. Specifically, we have shown that the stability of both p35, a neuronal protein that activates cdk5 through complex formation leading to aberrant Tau phosphorylation, and that of mutant but not WT Tau protein are maintained in tauopathies by Hsp90. Inhibition of Hsp90 in both cellular and mouse models of tauopathies led to reduction of the aberrant activity of these proteins and resulted in elimination of aggregated Tau. In addition, Chiosis laboratory has pioneered the discovery and development of synthetic Hsp90 inhibitors, the purine-scaffold inhibitors (PU-class), and has, in collaboration with a biotech, translated to clinic the first such agent, CNF-2024, an orally available small molecule currently in Phase I clinical evaluation in patients with cancers. These initial efforts have also identified PU-DZ8, a PU-Hsp90 inhibitor with favorable BBB- permeability profile. Administration of this molecule to Tau transgenic mice resulted in a reduction in toxic Tau aggregates. Based on these preliminary data, we propose here to further explore the significance of these Hsp90 inhibitors in tauopathies. First, we will explore whether a PU-DZ8 derivative with better Hsp90 affinity and improved CNS-drug like characteristics may be identified in the PU-series. Second, we will explore the functional significance of Hsp90 inhibition by these molecules in a Tau Tg mouse model and test whether PU-DZ8 may alleviate the neurodegenerative phenotype in tauopathy. For the successful completion of this aim we have co- opted Dr. Karen Duff to our team. Our proposal suggests Hsp90 inhibition as a novel therapeutic approach for increasing the survival of afflicted neurons and ameliorating the neurodegenerative phenotype. Considering that Hsp90 tightly regulates a protein only when it manifests aberrant function or stability, we propose that inhibition of Hsp90 by small molecules may confer a better therapeutic window than direct inhibition of kinase activity or suppression of Tau expression. Taken together with previous findings by Dou et al that Hsp90 inhibition induces Hsp70, a chaperone able to partition Tau into a productive folding pathway, our data portray Hsp90 inhibition as a double therapeutic modality in tauopathies in particular, or neurodegenerative disease in general. In conclusion, Hsp90- interfering drugs represent a potential novel class of drugs to promote the survival of neurons and open up a promising approach to the treatment of neurodegenerative diseases. [unreadable] [unreadable] [unreadable]